The sHunt for better breathing in heart failure with preserved ejection fraction.

Abstract

The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. This editorial refers to ‘Transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial pressure’, by L. Søndergaard et al., on page 796. Cardiovascular lesions may interact additively to cause haemodynamic duress, such as when the load induced by a stiff aorta adds in series with aortic valve stenosis to augment left ventricular (LV) pressure overload.1 Other lesions may be synergistic rather than additive, such as when a patient with mitral stenosis goes into atrial fibrillation (AF). Loss of left atrial (LA) contraction compromises LV filling and cardiac output, and, because the transvalvular gradient varies with the square of the filling period, attendant increases in heart rate cause marked LA hypertension.2 Some cardiac lesions may interact antagonistically. A century ago, Rene Lutembacher described patients with the rare combination of an atrial septal defect and mitral stenosis, and, since then, it has been recognized that people with this combination of lesions fair better and are less symptomatic than patients with isolated mitral stenosis, presumably because the shunt allows for LA decompression, even as forward LV output is reduced.3, 4 Like patients with mitral stenosis, people with heart failure and a preserved ejection fraction (HFpEF) suffer from LA hypertension. This can be very difficult to treat, because LA pressures are often normal at rest but increase only during the stress of exercise.5 Adding a diuretic might help minimize the LA hypertension with stress, but only at the cost of producing volume depletion and azotaemia since total body volume overload is generally not present in these patients.5 Vasodilators might help, but are associated with greater hypotensive effects and heightened vulnerability to stroke volume reduction in people with HFpEF.6 What is needed is an intervention that will preferentially reduce LA pressure when it is high, without compromising the adequacy of LV filling when LA pressure is closer to normal. In this issue of the journal, Sondegaard and colleagues provide exciting new data suggesting how we might leverage the ‘experiment of nature’ first described by Lutembacher to help treat people with HFpEF.7 In this small pilot study, a proprietary interatrial septal device (IASD; DC Devices Inc., Tewksbury, MA, USA) designed to decompress the left atrium through left to right shunting was implanted in patients with highly symptomatic HFpEF. A total of 11 subjects with definite HFpEF were enrolled, identified by elevated pulmonary capillary wedge pressure (PCWP) (≥15 mmHg at rest and/or ≥25 mmHg with exertion), normal or near-normal LVEF (>45%), diastolic dysfunction on echocardiography, and either prior HF hospitalization or severe chronic HF symptoms. Because of the plan to introduce a left to right shunt, patients with right ventricular (RV) dysfunction or significant pulmonary arterial (PA) hypertension (PA systolic >60 mmHg) were excluded. Resting haemodynamics, echocardiography, blood work, 6 min walk test, and quality of life were assessed at baseline prior to trans-septal deployment of the IASD, and at 30-day follow-up visits. The subjects enrolled were fairly representative of HFpEF in the community, with NYHA III–IV symptoms, mean age 70 years, hypertension in 91%, diabetes in 45%, and AF in 36%.7 Right atrial (RA) pressure, PCWP, and PA pressure were mildly elevated at study entry (12, 19, and 31 mmHg, respectively) with low–normal resting cardiac index (2.4 ± 0.4 L/min/m2), and borderline elevated pulmonary vascular resistance (4.9 ± 2.7 mmHg/m2/L). The primary objective of the study to demonstrate safety was accomplished: one device was initially maldeployed but was retrieved with a second device successfully implanted, and one subject was admitted with decompensated HF. There were no deaths, bleeding complications, or thrombo-embolic events reported, and devices remained patent at 30 days by echocardiography. Oxygen consumption (VO2) and systemic and mixed venous blood O2 contents were not assessed, so we cannot determine how much the shunt compromised systemic blood flow (Qs) or what the magnitude of shunting was (pulmonary to systemic flow ratio, Qp/Qs). While the secondary efficacy results must be interpreted cautiously given the lack of blinding and control group, there was an encouraging 28% reduction in resting PCWP noted, with no change in RA or PA pressures. Quality of life scores, NYHA class, and 6 min walk distance improved, while plasma NT-proBNP levels were unchanged. In summary, Sondergaard and colleagues showed that an IASD can be successfully deployed and appears to be safe through the first 30 days, with haemodynamic indicators suggesting potential for symptomatic benefit in patients with HFpEF.7 The authors are to be congratulated for completing this important pilot study, and the data provided serve to raise even more questions that will be answered by future studies. How will the left to right shunt created by the device affect exercise haemodynamics and, more importantly, exercise capacity? Kaye and colleagues recently published the results of a mathematical simulation performed using published HFpEF patient data from two studies5, 8 to predict the haemodynamic impact of IASD implantation.4 Resting PCWP was reduced in the simulation by a similar magnitude to that in the current study (30%) and exercise PCWP was reduced in the simulation from 28 to 17 mmHg, with minimal increase in RA pressure owing to the greater compliance of the RA–vena cava continuity. Exercise Qs dropped from 9.9 to 8.8 L/min in the model, which was coupled to a corresponding increase in Qp. In the simulation, PA pressures dropped by 18%, despite the increase in Qp, since downstream LA pressure dropped more than Qp increased. In this light, the lack of increase in resting PA pressures in the Sondergaard study is reassuring, though nothing can be concluded about changes in Qp or pulmonary vascular resistance owing to the lack of Fick outputs. There are potential concerns about the creation of an intracardiac shunt in HFpEF. One of the largest would be the development of worsening pulmonary hypertension and/or right heart failure. RV systolic dysfunction and remodelling is common in HFpEF.9 Melenovsky and colleagues have recently shown that the RV displays heightened afterload sensitivity in HFpEF, such that relatively minor increases in PA pressure are met with greater reductions in ejection capacity.10 Even in the absence of pressure overload, the volume load introduced by left to right shunting might favour eccentric right heart remodelling, worsening tricuspid regurgitation from annular deformation, and increasing risk of AF, which is also associated with RV dysfunction in HFpEF, independent of PA pressures.10 Indeed, one could envisage a Peter–Paul robbing type of situation in some patients, where left heart failure is exchanged for right-sided failure—this will need to be carefully evaluated for in future trials. In the discussion, the authors state that patients with HFpEF are generally not limited by cardiac output reserve,7 but in fact Abudiab and colleagues have recently shown that the increase in cardiac output relative to metabolic demand (ΔCO/ΔVO2) is substantially impaired on average in HFpEF, even though resting perfusion is normal and similar to controls.11 Thus in HFpEF patients with cardiac output limitation, the harm induced by an additional 10–15% reduction in Qs may outweigh any ostensible benefit from reduction in PCWP. However, HFpEF is a heterogenous disease, and some patients do not appear to be limited by cardiac output reserve.12 Success of the IASD will also be predicated on significant differences in LA and RA pressure (i.e. high trans-septal gradient), which fundamentally drives shunt flow. In this light, haemodynamic profiling through invasive exercise testing might help ensure identification of patients who are most (or least) likely to benefit from this novel therapeutic strategy (Figure 1). The hunt for solutions to managing HFpEF has been afoot for years, without much success to date. The findings of Sondergaard and colleagues7 offer new hope that we might not have to wait too much longer, and more data on this innovative approach are eagerly awaited. Conflict of interest: the author has served as an unpaid consultant to DC Devices.